Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish
Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell...
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The Company of Biologists
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doaj-ee5630c8439a4a52a7085e238f64e4e82020-11-25T01:43:43ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-05-0112510.1242/dmm.035790035790Disruption of asxl1 results in myeloproliferative neoplasms in zebrafishEvisa Gjini0Chang-Bin Jing1Ashley T. Nguyen2Deepak Reyon3Emma Gans4Michiel Kesarsing5Joshua Peterson6Olga Pozdnyakova7Scott J. Rodig8Marc R. Mansour9Keith Joung10A. Thomas Look11 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts 02215, USA Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell transformation, we generated asxl1 haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of asxl1 leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of bim and bid. Half of the asxl1+/− zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of asxl1 combined with heterozygous loss of tet2 led to a more penetrant MPN phenotype, while heterozygous loss of asxl1 combined with complete loss of tet2 led to acute myeloid leukemia (AML). These findings support the use of asxl1+/− zebrafish as a strategy to identify small-molecule drugs to suppress the growth of asxl1 mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of ASXL1.http://dmm.biologists.org/content/12/5/dmm035790ApoptosisHematopoietic stem cellsMyeloproliferative neoplasmsTet2Genome editing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Evisa Gjini Chang-Bin Jing Ashley T. Nguyen Deepak Reyon Emma Gans Michiel Kesarsing Joshua Peterson Olga Pozdnyakova Scott J. Rodig Marc R. Mansour Keith Joung A. Thomas Look |
spellingShingle |
Evisa Gjini Chang-Bin Jing Ashley T. Nguyen Deepak Reyon Emma Gans Michiel Kesarsing Joshua Peterson Olga Pozdnyakova Scott J. Rodig Marc R. Mansour Keith Joung A. Thomas Look Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish Disease Models & Mechanisms Apoptosis Hematopoietic stem cells Myeloproliferative neoplasms Tet2 Genome editing |
author_facet |
Evisa Gjini Chang-Bin Jing Ashley T. Nguyen Deepak Reyon Emma Gans Michiel Kesarsing Joshua Peterson Olga Pozdnyakova Scott J. Rodig Marc R. Mansour Keith Joung A. Thomas Look |
author_sort |
Evisa Gjini |
title |
Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
title_short |
Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
title_full |
Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
title_fullStr |
Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
title_full_unstemmed |
Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
title_sort |
disruption of asxl1 results in myeloproliferative neoplasms in zebrafish |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2019-05-01 |
description |
Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell transformation, we generated asxl1 haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of asxl1 leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of bim and bid. Half of the asxl1+/− zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of asxl1 combined with heterozygous loss of tet2 led to a more penetrant MPN phenotype, while heterozygous loss of asxl1 combined with complete loss of tet2 led to acute myeloid leukemia (AML). These findings support the use of asxl1+/− zebrafish as a strategy to identify small-molecule drugs to suppress the growth of asxl1 mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of ASXL1. |
topic |
Apoptosis Hematopoietic stem cells Myeloproliferative neoplasms Tet2 Genome editing |
url |
http://dmm.biologists.org/content/12/5/dmm035790 |
work_keys_str_mv |
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